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Farnesyltransferase inhibitors as radiation sensitizers
W Gillies McKenna1, Ruth J Muschel, Anjali K Gupta
1Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104, USA.
Abstract:
Activation of Ras, by mutation, overexpression, or by signaling through tyrosine kinase receptors, is associated with radioresistance. Thus, therapies that inhibit Ras function could be an effective means to radiosensitize selected types of solid tumors. Inhibition of Ras prenylation using a variety of farnesyltransferase inhibitors resulted in radiosensitization of tumor cells that expressed activated Ras, both in vitro and in xenograft models. Farnesyltransferase inhibitor treatment could also inhibit tumor regrowth following irradiation of mice bearing T24 tumor xenografts that express activated Ras. In a phase I trial of the farnesyltransferase inhibitor L-778-123 and radiotherapy in patients with locally advanced head and neck cancer and non-small cell lung cancer, a high response rate was observed coupled with a mild toxicity profile. Additional clinical trials should shed light on the potential of this and other farnesyltransferase inhibitors to serve as radiosensitizers and may identify molecular markers that could predict a response to these agents.
Insights
Farnesyltransferase inhibitors (FTIs) show promise in radiosensitizing tumors with activated Ras. Clinical trials indicate FTIs combined with radiotherapy yield high response rates and mild toxicity in head and neck and lung cancers.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Ras pathway activation, through mutation or signaling, correlates with radioresistance in solid tumors.
- Targeting Ras function offers a potential strategy to enhance tumor radiosensitization.
Purpose of the Study:
- To investigate the efficacy of farnesyltransferase inhibitors (FTIs) in radiosensitizing tumors with activated Ras.
- To evaluate the potential of FTIs as adjuncts to radiotherapy in preclinical models and clinical trials.
Main Methods:
- In vitro and xenograft models of tumors expressing activated Ras were treated with FTIs.
- Tumor regrowth inhibition was assessed following irradiation and FTI treatment.
- A Phase I clinical trial combined L-778-123 (an FTI) with radiotherapy in patients with advanced head and neck and non-small cell lung cancer.
Main Results:
- FTI treatment demonstrated radiosensitization of tumor cells with activated Ras in vitro and in vivo.
- FTI treatment inhibited tumor regrowth after irradiation in mice bearing T24 tumor xenografts.
- The Phase I trial showed a high response rate and mild toxicity profile for L-778-123 and radiotherapy.
Conclusions:
- Inhibition of Ras prenylation via FTIs can radiosensitize tumors with activated Ras.
- FTIs represent a promising therapeutic strategy for enhancing radiotherapy efficacy.
- Further clinical trials are warranted to confirm the role of FTIs as radiosensitizers and identify predictive biomarkers.